Cerebral Small Vessel Disease (SVD) is a vascular disorder that contributes to approximately 50% of human dementias world-wide. Once initiated, SVD proceeds ineluctably towards its conclusion. Preventing the onset or progression of cerebrovascular dysfunction is hampered by our lack of knowledge of the molecular and cellular mechanisms that underlie basic vascular pathobiology. SVD is caused by hypoxic hypoperfusion that underlies the etiology and is characterized by progressive white matter lesions (WML) in the brain?s subcortical structures. Human studies indicated that blood-brain barrier (BBB) dysfunction plays a causative role in SVD pathology and is likely the link between hypoxic hypoperfusion and the WML. Hence, we ask whether reversal of BBB damage will be accompanied by an improvement in the progression of SVD pathology, and how this reversal could be accomplished. Sphingosine 1 phosphate (S1P), a signaling sphingolipid, is a key regulator of BBB function through binding to its receptors (S1PR1-5). Activation of S1PR1 by S1P promotes vascular maturation, stabilization and assembly of endothelial tight junctions (TJs) and adherens junctions (AJs), reduces BBB leakage, and limits leukocyte infiltration. Reversal of BBB dysfunction in SVD may be possible by targeting the S1PR1 pathway, however, its effect on BBB dysfunction in SVD and other vascular dementias has not been examined. The objective of this proposal is to determine if agonist-induced activation of S1PR1 will reverse hypoxic hypoperfusion-induced BBB disruption, reduce inflammation, and ameliorate WML formation and cognitive deficits. Our central hypothesis is that chronic hypoxic hypoperfusion downregulates capillary endothelial S1PR1, disrupting endothelial TJs/AJs, leading to BBB dysfunction and neuroinflammation. We will test our hypothesis in a spontaneously hypertensive rat-stroke prone (SHRSP) model. Our published studies documented the hypoxia with electron paramagnetic resonance, the WML and BBB damage with serial MRIs, and the cognitive impairment in the SHRSPs, similar to those in SVD when the SHRSPs are subjected to Japanese Permissive Diet (JPD) and unilateral carotid occlusion (UCAO). Aim 1 is to determine whether S1PR1 activation by the selective agonist SEW2871 will preserve BBB permeability. Aim 2 is to determine whether S1PR1 activation will enhance endothelial cell junctions and limit immune cell infiltration. Aim 3 is to determine whether S1PR1 activation enhances BBB integrity by reducing EC apoptosis, as well as by promoting EC proliferation, cytoskeletal reorganization, and angiogenesis. The premise for this proposal focuses on, for the first time, on unraveling the novel mechanisms involving the S1P-S1PR axis as a means to prevent progressive neurodegeneration and cognitive deficits in SVD through the reversal of BBB disruption. Using a unique model and innovative approaches, the proposed work aims to fill significant gaps in our understanding of the mechanisms of capillary and BBB dysfunction in SVD. The proposed research is significant since this area of study fits well within the goals of NIH NINDS and has direct implications for global health.